Disubstituted acetylenes bearing a diazinyl group having retinoid like activity

ABSTRACT

Retinoid-like activity is exhibited by compounds of the formula ##STR1## where X is S, O, or NR&#39; where R&#39; is hydrogen or lower alkyl; R is hydrogen or lower alkyl; A is pyridazinyl, pyrimidinyl or pyrazinyl; n is 0-4; and B is H, --COOH or a pharmaceutically acceptable salt, ester or amide thereof, --CH 2  OH or an ether or ester derivative, or --CHO or an acetal derivative, or --COR 1  or a ketal derivative where R 1  is --(CH 2 ) m  CH 3  where m is 0-4, or a pharmaceutically acceptable salt thereof.

CROSS-REFERENCED TO RELATED APPLICATIONS

This is a continuation of application Ser. No. 08,027,625 filed on Mar.8, 1993 and abandoned in favor of this continuation application, whichwas a divisional of pending application Ser. No. 07/792,832 filed onNov. 15, 1991 which issued as U.S. Pat. No. 5,234,926 which, in turn wasa divisional of application Ser. No. 326,191 filed on Mar. 20, 1989, nowissued as U.S. Pat. No. 5,089,509, which was a continuation-in-part ofU.S. application Ser. No. 07/246,037 filed Sep. 15, 1988 now abandoned,which in turn was a continuation of application Ser. No. 028,279 filedon Mar. 20, 1987, now abandoned.

BACKGROUND

This invention relates to novel compounds having retinoid-like activity.More specifically, the invention relates to compounds having anethynylheteroaromatic acid portion and a second portion which is atetrahydroquinolinyl, thiocromanyl, or chromanyl group. The acidfunction may also be converted to an alcohol, aldehyde or ketone orderivatives thereof, or may be reduced to --CH₃.

RELATED ART

Carboxylic acid derivatives useful for inhibiting the degeneration ofcartilage of the general formula4-(2-(4,4-dimethyl-6-X)-2-methylvinyl)benzoic acid where X istetrahydroquinolinyl, chromanyl or thiochromanyl are disclosed inEuropean Patent Application 0133795 published Jan. 9, 1985. See alsoEuropean Patent Application 176034A published Apr. 2, 1986 wheretetrahydronaphthalene compounds having an ethynylbenzoic acid group aredisclosed.

SUMMARY OF THE INVENTION

This invention covers compounds of formula I ##STR2## wherein X is S, O,or NR' where R' is hydrogen or lower alkyl; R is hydrogen or loweralkyl; A is pyridinyl, thienyl, furyl, pyridazinyl, pyrimidinyl orpyrazinyl; n is 0-2; and B is H, --COOH or a pharmaceutically acceptablesalt, ester or amide thereof, --CH₂ OH or an ether or ester derivative,or --CHO or an acetal derivative, or --COR₁ or a ketal derivative whereR₁ is --(CH₂)_(m) CH₃ where m is 0-4.

In a second aspect, this invention relates to the use of the compoundsof formula I for treating dermatoses, such as acne, Darier's disease,psoriasis, icthyosis, eczema, atopic dermatitis and epithelial cancers.These compounds are also useful in the treatment of arthritic diseasesand other immunological disorders (e.g., lupus erythematosus), inpromoting wound healing, in treating dry eye syndrome and in reversingthe effects of sun damage to skin.

This invention also relates to a pharmaceutical formulation comprising acompound of formula I in admixture with a pharmaceutically acceptableexcipient.

In another aspect, this invention relates to the process for making acompound of formula I which process comprises reacting a compound offormula II with a compound of formula III in the presence of cuprousiodide and Pd(PQ₃)₂ Cl₂ or a similar complex where the two formulas arerepresented by graphics II and III ##STR3## where X' is a halogen,preferably I; n and A are the same as defined above; and B is H, or aprotected acid, alcohol, aldehyde or ketone, giving the correspondingcompound of formula I; or to the process of making a compound of formulaI which consists of reacting a zinc salt of formula IV with a compoundof formula III in the presence of Pd(PQ₃)₄ (Q is phenyl) or a similarcomplex, ##STR4## giving the corresponding compound of formula I; orhomologating a compound of the formula ##STR5## where n is 0-1 to givean acid of formula I; or converting an acid of formula I to a salt; or

forming an acid addition salt;

converting an acid of formula I to an ester; or

converting an acid of formula I to an amide; or

reducing an acid of formula I to an alcohol or aldehyde; or

converting an alcohol of formula I to an ether or ester; or

oxidizing an alcohol of formula I to an aldehyde; or

converting an aldehyde of formula I to an acetal; or

converting a ketone of formula I to a ketal.

GENERAL EMBODIMENTS Definitions

The term "ester" as used here refers to and covers any compound fallingwithin the definition of that term as classically used in organicchemistry. Where A is --COOH, this term covers the products derived fromtreatment of this function with alcohols. Where the ester is derivedfrom compounds where A is --CH₂ OH, this term covers compounds of theformula --CH₂ OOCR where R is any substituted or unsubstitutedaliphatic, aromatic or aliphatic-aromatic group.

Preferred esters are derived from the saturated aliphatic alcohols oracids of ten or fewer carbon atoms or the cyclic or saturated aliphaticcyclic alcohols and acids of 5 to 10 carbon atoms. Particularlypreferred aliphatic esters are those derived from lower alkyl acids an,alcohols. Here, and where ever else used, lower alkyl means having 1-6carbon atoms. Also preferred are the phenyl or lower alkylphenyl esters.

Amide has the meaning classically accorded that term in organicchemistry. In this instance it includes the unsubstituted amides and allaliphatic and aromatic mono- and di-substituted amides. Preferred amidesare the mono- and di-substituted amides derived from the saturatedaliphatic radicals of ten or fewer carbon atoms or the cyclic orsaturated aliphatic-cyclic radicals of 5 to 10 carbon atoms.Particularly preferred amides are those derived from lower alkyl amines.Also preferred are mono- and di-substituted amides derived from thephenyl or lower alkylphenyl amines. Unsubstituted amides are alsopreferred.

Acetals and ketals includes the radicals of the formula --CK where K is(--OR)₂. Here, R is lower alkyl. Also, K may be --OR₁ O-- where R₁ islower alkyl of 2-5 carbon atoms, straight chain or branched.

A pharmaceutically acceptable salt may be prepared for any compound ofthis invention having a functionality capable of forming such salt, forexample an acid or an amine functionality. A pharmaceutically acceptablesalt may be any salt which retains the activity of the parent compoundand does not impart any deleterious or untoward effect on the subject towhich it is administered and in the context in which it is administered.

Such a salt may be derived from any organic or inorganic acid or base.The salt may be a mono or polyvalent ion. Of particular interest wherethe acid function is concerned are the inorganic ions, sodium,potassium, calcium, and magnesium. Organic amine salts may be made withamines, particularly ammonium salts such as mono-, di- and trialkylamines or ethanol amines. Salts may also be formed with caffeine,tromethamine and similar molecules. Where there is a nitrogensufficiently basic as to be capable of forming acid addition salts, suchmay be formed with any inorganic or organic acids or alkylating agentsuch as methyl iodide. Preferred salts are those formed with inorganicacids such as hydrochloric acid, sulfuric acid or phosphoric acid. Anyof a number of simple organic acids such as a mono-, di- or tri-acid mayalso be used.

The preferred compounds of this invention are those where the ethynylgroup and the B group are attached to the 2 and 5 positions respectivelyof a pyridine ring (the 6 and 3 positions in the nicotinic acidnomenclature being equivalent to the 2/5 designation in the pyridinenomenclature) or the 5 and 2 positions respectively of a thiophene grouprespectively; n is 0; and B is --COOH, an alkali metal salt or organicamine salt, or a lower alkyl ester, or --CH₂ OH and the lower alkylesters and ethers thereof, or --CHO and acetal derivatives thereof.

The most preferred compounds are:

ethyl 6-(2-(4,4-dimethylthiochroman-6-yl)ethynyl)nicotinate;

6-(2-(4,4-dimethylthiochroman-6-yl)ethynyl)nicotinic acid;

6-(2-(4,4-dimethylchroman-6-yl)ethynyl)nicotinic acid;

ethyl 6-(2-(4,4-dimethylchroman-6-yl)ethynyl)nicotinate;

ethyl 6-(2-(4,4,7-trimethylthiochroman-6-yl)-ethynyl)nicotinate;

ethyl 6-(2-(4,4-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)ethynyl)nicotinate;

ethyl5-(2-(4,4-dimethylthiochroman-6-yl)ethynyl)thiophene-2-carboxylate.

6-(2-(4,4-dimethylthiochroman-6-yl)-ethynyl)-3-pyridylmethanol; and

2-(2-(4,4-dimethylthiochroman-6-yl)-ethynyl)-5-pyridinecarboxaldehyde.

The compounds of this invention may be administered systemically ortopically, depending on such considerations as the condition to betreated, need for site-specific treatment, quantity of drug to beadministered, and similar considerations.

In the treatment of dermatoses, it will generally be preferred toadminister the drug topically, though in certain cases such as treatmentof severe cystic acne, oral administration may also be used. Any commontopical formulation such as a solution, suspension, gel, ointment, orsalve and the like may be used. Preparation of such topical formulationsare well described in the art of pharmaceutical formulations asexemplified, for example, Remington's Pharmaceutical Science, Edition17, Mack Publishing Company, Easton, Pa. For topical application, thesecompounds could also be administered as a powder or spray, particularlyin aerosol form.

If the drug is to be administered systemically, it may be confected as apowder, pill, tablet or the like, or as a syrup or elixir for oraladministration. For intravenous or intraperitoneal administration, thecompound will be prepared as a solution or suspension capable of beingadministered by injection. In certain cases, it may be useful toformulate these compounds in suppository form or as an extended releaseformulation for deposit under the skin or intermuscular injection.

Other medicaments can be added to such topical formulation for suchsecondary purposes as treating skin dryness, providing protectionagainst light; other medications for treating dermatoses, preventinginfection, reducing irritation, inflammation and the like.

Treatment of dermatoses or any other indications known or discovered tobe susceptible to treatment by retinoic acid-like compounds will beeffected by administration of the therapeutically effective dose of oneor more compounds of the instant invention. A therapeutic concentrationwill be that concentration which effects reduction of the particularcondition, or retards its expansion. In certain instances, the drugpotentially could be used in a prophylactic manner to prevent onset of aparticular condition. A given therapeutic concentration will vary fromcondition to condition and in certain instances may vary with theseverity of the condition being treated and the patient's susceptibilityto treatment. Accordingly, a given therapeutic concentration will bebest determined at the time and place through routine experimentation.However, it is anticipated that in the treatment of, for example, ache,or other such dermatoses, that a formulation containing between 0.001and 5 percent by weight, preferably about 0.01 to 1%, will usuallyconstitute a therapeutically effective concentration. If administeredsystemically, an amount between 0.01 and 100 mg per kg body weight perday, but preferably about 0.1 to 10 mg/kg, will effect a therapeuticresult in most instances.

The retinoic acid like activity of these compounds was confirmed throughthe classic measure of retinoic acid activity involving the effects ofretinoic acid on ornithine decarboxylase. The original work on thecorrelation between retinoic acid and decrease in cell proliferation wasdone by Verma & Boutwell, Cancer Research, 1977, 37, 2196-2201. Thatreference discloses that ornithine decarboxylase (ODC) activityincreased precedent to polyamine biosynthesis. It has been establishedelsewhere that increases in polyamine synthesis can be correlated orassociated with cellular proliferation. Thus, if ODC activity could beinhibited, cell hyperproliferation could be modulated. Although allcauses for ODC activity increase are unknown, it is known that12-0-tetradecanoyl-phorbol-13-acetate (TPA) induces ODC activity.Retinoic acid inhibits this induction of ODC activity by TPA. Thecompounds of this invention also inhibit TPA induction of ODC asdemonstrated by an assay essentially following the procedure set out inCancer Res.: 1662-1670, 1975.

SPECIFIC EMBODIMENTS

The compounds of this invention can be made by a number of differentsynthetic chemical pathways. To illustrate this invention, there is hereoutlined a series of steps which have been proven to provide thecompounds of formula I when such synthesis is followed in fact and inspirit. The synthetic chemist will readily appreciate that theconditions set out here are specific embodiments which can begeneralized to any and all of the compounds represented by formula I.Compounds of formula I where X is --S-- are prepared as per ReactionScheme I. ##STR6## Here, R is hydrogen or a lower alkyl group, A isdefined above, n is 0-2 and B is H, or a protected acid, alcohol,aldehyde or ketone. X' is Cl, Br s or I when n is 0 but preferably is Bror I when n is 1 or 2.

Alternatively, compounds of formula I where X is --S-- are prepared asper Reaction Scheme II ##STR7## The definitions of R, n, A, B and X' arethe same here as in Reaction Scheme I.

Compounds of formula I where X is oxygen are prepared as per ReactionScheme III. ##STR8## The definitions of R, n, A, B and X' are the samehere as in Scheme I.

Compounds of formula I where X is N--R' where R' is hydrogen or alkylare prepared as per Reaction Scheme IV. ##STR9## The definitions of R',n, A, B and X' are the same here as in Scheme I.

Alternatively, the sequence of steps outlined in Reaction Scheme V willserve to make such compounds where X is N--R' and R' is H or loweralkyl. ##STR10##

A general description for making each of the compounds recited in theforegoing Reaction Schemes follows.

In Reaction Scheme I, the following generalized reaction conditions areapplicable. The thiophenol of formula 1 is first treated withapproximately an equimolar amount of a strong base such as an alkalimetal hydroxide, preferably sodium hydroxide, in acetone at reflux.Refluxing is carried out for between 1 and 4 hours, preferably 2.5hours, after which the solution is treated with an equimolar amount offormula 2, 1-bromo-3-methyl-2-butene (Aldrich), dissolved in acetone.Refluxing is continued for about 2 days after which the solution isstirred for another 24 hours at about room temperature effectingformation of formula 3. It is isolated by conventional means.

Ring closure is effected by treating the sulfide (compound 3), whoseformation is described above, with phosphorous pentoxide in the presenceof phosphoric acid under an inert atmosphere to give the thiochroman offormula 4. The sulfide is first dissolved in an inert solvent such asbenzene, toluene, or the like, and then treated with a small excess ofphosphorous pentoxide along with concentrated phosphoric acid. Thesolution is heated at reflux with stirring under an inert gas such asargon or nitrogen for up to 24 hours. The product is then recovered andpurified by conventional means.

The ketone of formula 5 is obtained by treating the thiochroman withacetyl chloride in the presence of aluminum chloride. A suspension ofthe aluminum chloride in a polar inert solvent is prepared under aninert atmosphere and at reduced temperature, i.e., -10° to 10° C. Theinert atmosphere may be argon or nitrogen, preferably argon. Thereaction is conveniently carried out in a solvent such as methylenechloride. To the aluminum chloride suspension is added the thiochromanand acetyl chloride via a dropping funnel or similar device. About a 5%molar excess of acetyl chloride and 10% molar excess of aluminumchloride, relative to the thiochroman material, is used. The reaction iseffected with agitation (stirring) over 0.5-4 hours at a temperaturebetween 10°-50° C. Preferably the reaction is effected in about 2 hoursat room temperature. Then the reaction is quenched with water and/orice, the product extracted and further purified by distillation or someother appropriate means.

The acetylenic function of formula 6 is introduced by means of lithiumdiisopropylamide or a similar base at reduced temperature under an inertatmosphere. The reaction is carried out in an ether-type of solvent suchas a dialkyl ether or a cyclic ether, for example, tetrahydrofuran,pyran or the like.

More specifically, lithium diisopropylamide is generated in situ bymixing diisopropylamine in a dry solvent such as tetrahydrofuran, whichis then cooled, to between -70° and -50° C. under an inert atmosphere.An equimolar amount of an alkylithium compound such as n-butyl lithiumin an appropriate solvent is then added at the reduced temperature andmixed for an appropriate time to permit formation of lithiumdiisopropylamide (LDA). The ketone of formula 5 (at least a 10% molarexcess) is dissolved in the reaction solvent, the solution cooled tothat of the LDA mixture, and added to that solution. After brief mixing,the solution is then treated with a dialkyl chlorophosphate, preferablydiethyl chlorophosphate in about a 20% molar excess. The reactionsolution is then gradually brought to room temperature. This solution isthen added to a second lithium diisopropylamide Solution which isprepared in situ using dry solvent all under an inert atmosphere,preferably argon, at reduced temperature (e.g. -78° C.). Thereafter, thereaction mixture is again warmed to room temperature where it is stirredfor an extended period of time, preferably between 10 and 20 hours, mostpreferably about 15 hours. The solution is then acidified and theproduct recovered by conventional means.

Formula 7 compounds are prepared under conditions which exclude waterand oxygen. A dry, ether-type solvent such as dialkyl ether or a cyclicether such as a furan or pyran, particularly a tetrahydrofuran, may beused as the solvent. A solution of formula 6 is first prepared under aninert atmosphere such as argon or nitrogen, and then a strong base suchas n-butyl lithium is added (in about a 10% molar excess). This reactionis begun at a reduced temperature of between -10° and +10° C.,preferably about 0° C. The reaction mixture is stirred for a shortperiod, between 30 minutes and 2 hours, and then treated with about a10% molar excess of fused zinc chloride dissolved in the reactionsolvent. This mixture is stirred for an additional 1-3 hours at aboutthe starting temperature, then the temperature is increased to aboutambient temperature for 10-40 minutes.

Where a protected heteroaromatic compound is needed to couple withformula 7 compounds, such may be prepared from their correspondingacids, alcohols, ketones or aldehydes. These starting materials, theprotected acids, alcohols, aldehydes or ketones, are all available fromchemical manufacturers or can be prepared by published methods. Acidsare esterified by refluxing the acid in a solution of the appropriatealcohol in the presence of thionyl chloride. Refluxing for 2-5 hoursprovides the desired ester. Alternatively, the acid can be condensedwith the appropriate alcohol in the presence of dicyclohexylcarbodiimideand dimethylaminopyridine. The ester is recovered and purified byconventional means. Acetals and ketals are readily made by the methoddescribed in March, "Advanced Organic Chemistry," 2nd Edition,McGraw-Hill Book Company, p 810). Alcohols, aldehydes and ketones allmay be protected by forming respectively, ethers and esters, acetals orketals by known methods such as those described in McOmie, PlenumPublishing Press, 1973 and Protecting Groups, Ed. Greene, John Wiley &Sons, 1981.

To increase the value of n before effecting a coupling reaction, wheresuch compounds are not available from a commercial source, theheteroaromatics where B is --COOH are subjected to homologation bysuccessive treatment under Arndt-Eistert conditions or otherhomologation procedures. These acids are then esterified by the generalprocedure outlined in the preceding paragraph. Alternatively,heteroaromatics where B is a different functional may also behomologated by appropriate procedures.

To effect the coupling of the thiochroman moiety with those of formulaIII, the halo-substituted heteroaromatic compound is dissolved in a dryreaction solvent. The heteromatic compound is used in an amountapproximating the molar concentration of formula 7. This solution isintroduced into a suspension of tetrakis-triphenylphosphine palladium(about a 5 to 10% molar amount relative to the reactants) in thereaction solvent at a temperature of between about -10° and +10° C. Thismixture is stirred briefly, for about 15 minutes. To this just preparedmixture is then added the pre-prepared solution of formula 7, theaddition being made at about room temperature. This solution is stirredfor an extended period, between about 15 and 25 hours at roomtemperature. The reaction is then quenched with acid and the productseparated and purified by conventional means to give the compounds offormula I.

An alternative means for making compounds where n is 1 or 2 is tosubject the compounds of formula I where B is an acid or other functionto homologation using the Arndt-Eistert method referred to above orother homologation procedures.

The acids and salts derived from formula I are readily obtainable fromthe corresponding esters. Basic saponification with an alkali metal basewill provide the acid. For example, an ester of formula I may bedissolved in a polar solvent such as an alkanol, preferably under aninert atmosphere at room temperature, with about a three molar excess ofbase, for example, potassium hydroxide. The solution is stirred for anextended period of time, between 15 and 20 hours, cooled, acidified andthe hydrolysate recovered by conventional means.

The amide may be formed by any appropriate amidation means known in theart. One way to prepare such compounds is to convert an acid to an acidchloride and then treat that compound with ammonium hydroxide or anappropriate amine. For example, the acid is treated with an alcoholicbase solution such as ethanolic KOH (in approximately a 10% molarexcess) at room temperature for about 30 minutes. The solvent is removedand the residue taken up in an organic solvent such as diethyl ether,treated with a dialkyl formamide and then a 10-fold excess of oxalylchloride. This is all effected at a moderately reduced temperaturebetween about -10° and +10° C. The last mentioned solution is thenstirred at the reduced temperature for 1-4 hours, preferably 2 hours.Solvent removal provides a residue which is taken up in an inertinorganic solvent such as benzene, cooled to about 0° C. and treatedwith concentrated ammonium hydroxide. The resulting mixture is stirredat a reduced temperature for 1-4 hours. The product is recovered byconventional means.

Alcohols are made by converting the corresponding acids to the acidchloride with thionyl chloride or other means (J. March, "AdvancedOrganic Chemistry", 2nd Edition, McGraw-Hill Book Company), thenreducing the acid chloride with sodium borohydride (March, Ibid, pg.1124), which gives the corresponding alcohols. Alternatively, esters maybe reduced with lithium aluminum hydride at reduced temperatures.Alkylating these alcohols with appropriate alkyl halides underWilliamson reaction conditions (March, Ibid, pg. 357) gives thecorresponding ethers. These alcohols can be converted to esters byreacting them with appropriate acids in the presence of acid catalystsor dicyclohexylcarbodiimide and dimethylaminopyridine.

Aldehydes can be prepared from the corresponding primary alcohols usingmild oxidizing agents such as pyridinium dichromate in methylenechloride (Corey, E. J., Schmidt, G., Tet. Lett., 399, 1979), or dimethylsulfoxide/oxalyl chloride in methylene chloride (Omura, K., Swern, D.,Tetrahedron, 1978, 34, 1651).

Ketones can be prepared from an appropriate aldehyde by treating thealdehyde with an alkyl Grignard reagent or similar reagent followed byoxidation.

Acetals or ketals can be prepared from the corresponding aldehyde orketone by the method described in March, Ibid, p 810.

Compounds where B is H are prepared from the correspondinghalo-heterocyclic entity preferably where the halogen is I, Thishaloheterocyclic compound is reacted with the ethynyl entity or theethynyl zinc chloride entity as represented in Reaction Scheme I and asillustrated in the Examples, Halo-substituted heterocyclic compoundswhere B is H are commercially available or can be prepared by methods inthe literature,

Compounds where X is oxygen are prepared by the steps outlined inReaction Scheme III. The phosphate of formula 14 is prepared from thecorresponding diphenyl chlorophosphate and 3-methyl-3-butene-1-olavailable from Aldrich or which may be prepared by means known in theart. It is preferred to prepare formula 14 by dissolving the alcohol offormula 13 in about a 10% excess of pyridine in a polar inert solventunder an inert atmosphere cooled to approximately -10° to 10° C. Thissolution is then added drop-wise, under an inert atmosphere, to asolution of cooled diphenyl chlorophosphate in about an equal amount ofthe reaction solvent. About a 2-5% molar excess of diphenylchlorophosphate relative to the alcohol is employed. The atmosphere maybe argon, nitrogen, or another inert gas. The mixture is heated atreflux for between 1 and 5 hours, preferably about 3, to effect thereaction. The product is then recovered by conventional means.

The diphenyl phosphate ester from the preceding paragraph (formula 14)is then reacted with phenol or 3-alkylphenol to effect formation ofcompound 16. For example, phenol is added to a flask already containingstannic chloride under argon which has been cooled to between -10° to10° C. After thorough mixing of this combination for about 15 minutes toan hour at the reduced temperature, the phosphate is added at thereduced temperature. Both of these steps are carried out under an inertatmosphere such as argon or nitrogen. When the addition of the phosphateis completed, the mixture is stirred at about ambient temperature for upto 24 hours. Then the reaction is quenched with a dilute solution ofaqueous alkali metal base or the like. The product is recovered byextraction and other conventional means.

Formula 16 is then acetylareal, converted to the acetylene and eitherthe acetylene or the corresponding alkynyl zinc chloride salt coupledwith the appropriate heterocycle by the steps outlined in ReactionScheme I.

The tetrahydroquinoline moiety, that is where X is nitrogen, can be madeby the steps outlined in Reaction Scheme IV in part by the methoddescribed in European Patent Application 0130795 published Sep. 1, 1985.First, 3-methylcrotonoyl chloride is reacted with aniline to obtain theamide. This amide is then cyclized using aluminum chloride in theabsence of solvent. Lithium aluminum hydride or another acceptablereducing agent of similar type is then used to reduce the2-oxo-1,2,3,4-tetrahydroquinoline, preferably in an inert solvent suchas diethyl ether. This amine is then acetylated using acetyl chloride ina polar solvent such as pyridine. This protected amine is thenacetylareal in the presence of aluminum chloride. The acetyl function onthe nitrogen may then be removed by base hydrolysis. Then theacetylareal compound is converted to the acetylene and ZnCl salt asoutlined in Reaction Scheme I. The acetylene or the salt is then coupledwith an appropriate compound of formula III as described before to givecompounds of formula I.

Reaction Scheme V sets out an alternative method for making thetetrahydroquinoline compounds illustrated in Reaction Scheme IV.

The following Examples are set out to illustrate the invention, not tolimit its scope.

EXAMPLE 1 Phenyl-3-methylbut-2-enylsulfide

A mixture of 14.91 g (135.324 mmol) of thiophenol and 5.5 g (137.5 mmol)of NaOH in 100 ml acetone was heated at reflux for 2.5 hours and thentreated dropwise with a solution of 20 g (134.19 mmol) of1-bromo-3-methyl-2-butene in 20 ml acetone. This solution was refluxedfor 40 hours and then stirred at room temperature for 24 hours. Solventwas then removed in vacuo, the residue taken up in water, and extractedwith 3×50 ml ether. Ether extracts were combined and washed with 3×30 mlof 5% NaOH solution, then water, saturated NaCl solution and dried(MgSO₄). Solvent was then removed in vacuo and the residue furtherpurified by kugelrohr distillation (80° C., 0.75 mm) to give the titlecompound as a pale yellow oil.

PMR (CDCl₃): δ 1.57 (3H, s), 1.69 (3H, s), 3.52 (2H, d, J˜7.7 Hz), 5.29(1H, t, J˜7.7 Hz), 7.14 (1H, t, J˜7.0 Hz), 7.24 (2H, t, J˜7.0 Hz), 7.32(2H, d, J˜7.0 Hz).

EXAMPLE 2 4,4-Dimethylthiochroman

To a solution of 15.48 g (86.824 mmol) ofphenyl-3-methylbut-2-enylsulfide (from Example 1) in 160 ml benzene wereadded successively 12.6 g (88.767 mmol) of phosphorus pentoxide and 11ml of 85% phosphoric acid. This solution was refluxed with vigorousstirring under argon for 20 hours, then cooled to room temperature. Thesupernatant organic layer was decanted and the syrupy residue extractedwith 3×50 ml ether. Organic fractions were combined and washed withwater, saturated NaHCO₃ and saturated NaCl solution and then dried(MgSO₄). Solvent was removed in vacuo and the residue purified bykugelrohr distillation (80° C., 0.5 mm) to give the title compound as apale yellow oil.

PMR (CDCl₃): δ 1.30 (6H, s), 1.90-1.95 (2H, m), 2.95-3.00 (2H, m),6.96-7.00 (2H, m), 7.04-7.07 (1H, m), 7.30-7.33 (1H, m).

This method can be used to make 7-position alkyl analogues asexemplified by the following compounds:

4,4,7-trimethylthiochroman;

4,4-dimethyl-7-ethylthiochroman;

4,4-dimethyl-7-propylthiochroman;

4,4-dimethyl-7-butylthiochroman; and

4,4-dimethyl-7-hexylthiochroman.

EXAMPLE 3 4,4 Dimethyl-6-acetylthiochroman

A solution of 14.3 g (80.21 mmol) of 4,4-dimethyl thiochroman (fromExample 2) and 6.76 g (86.12 mmol) of acetyl chloride in 65 ml benzenewas cooled in an ice bath and treated dropwise with 26.712 g (102.54mmol) of stannic chloride. The mixture was stirred at room temperaturefor 12 hours, then treated with 65 ml water and 33 ml conc. hydrogenchloride and heated at reflux for 0.5 hours. After being cooled to roomtemperature, the organic layer was separated and the aqueous layerextracted with 5×50 ml benzene. The recovered organic fractions werecombined and washed with 5% sodium carbonate solution, water, saturatedNaCl solution and then dried (MgSO₄). The solvent was removed in vacuoand the residue purified by flash chromatography (silica; 5% ethylacetate in hexanes) followed by kugelrohr distillation (150° C., 0.7 mm)to give the title compound as a pale yellow oil.

PMR (CDCl₃): δ 1.35 (6H, s), 1.92-1.98 (2H, m) 2.54 (3H, s), 3.02-3.08(2H, m), 7.13 (1H, d, J˜8.6 Hz), 7.58 (1H, dd, J˜8.6 Hz, 2 Hz), 7.99(1H, d, J˜2 Hz).

This same method may be used to acetylate all compounds made as perExample 2.

EXAMPLE 4 4.4-Dimethyl-6-ethynylthiochroman

To a solution of 1.441 g (14.2405 mmol) of diisopropylamine in 30 ml drytetrahydrofuran under argon at -78° C. was added dropwise 9 ml of 1.6M(14.4 mmol) n-butyllithium in hexane. After stirring this solution at-78° C. for 1 hour, it was treated dropwise with a solution of 2.95 g(13.389 mmol) of 4,4-dimethyl-6-acetylthiochroman in 5 ml of drytetrahydrofuran. After another hour of stirring at -78° C., the solutionwas treated with 2.507 g (14.53 mmol) of diethyl chlorophosphate andbrought to room temperature, where it was stirred for 3.75 hours. Thissolution was then transferred using a double ended needle to a solutionof lithium diisopropylamide (prepared as above using 2.882 g (28.481mmol) of diisopropylamine and 18 ml of 1.6M (28.8 mmol) n-butyllithiumin hexane) in 60 ml dry tetrahydrofuran at -78° C. The cooling bath wasremoved and the solution stirred at room temperature for 15 hours, thenquenched with water and acidified to pH 1 with 3N hydrogen chloride. Themixture was stirred at room temperature for 12 hours, then treated with65 ml water and 33 ml conc. hydrogen chloride and heated at reflux for0.5 hours. After being cooled to room temperature, the organic layer wasseparated and the aqueous layer extracted with 5×50 ml benzene. Therecovered organic fractions were combined and washed with 5% sodiumcarbonate solution, water, saturated NaCl solution and then dried(MgSO₄). The solvent was removed in vacuo and the residue purified byflash chromatography (silica; 5% ethyl acetate in hexanes) followed bykugelrohr distillation (150° C., 0.7 mm) to give the captioned compoundas a pale yellow oil.

PMR, (CDCl₃): δ 1.35 (6H, s), 1.92-1.98 (2H, m) 2.54 (3H, s), 3.02-3.08(2H, m), 7.13 (1H, d, J˜8.6 Hz), 7.58 (1H, dd, J˜8.6 Hz, 2 Hz), 7.99(1H, d, J˜2 Hz).

In the same manner, all acetyl-containing compounds prepared underExample 3 may be converted to their corresponding ethynyl analogues.

EXAMPLE 5 Ethyl 6-chloronicotinate

A mixture of 15.75 g (0.1 mol) 6-chloronicotinic acid, 6.9 g (0.15 mol)ethanol, 22.7 g (0.11 mol) dicyclohexylcarbodiimide and 3.7 gdimethylaminopyridine in 200 ml methylene chloride was heated at refluxfor 2 hours. The mixture was allowed to cool, solvent removed in vacuoand residue subjected to flash chromatography to give the title compoundas a low-melting white solid.

PMR (CDCl₃): δ 1.44 (3H, t, J˜6.2 Hz) 4.44 (2H, q, J˜4.4 Hz), 7.44 (1H,d, J˜8.1 Hz), 8.27 (1H, dd, J˜8.1 Hz, 3 Hz), 9.02 (1H, d, J˜3 Hz).

This procedure may be used to esterify any of the other halo-substitutedacids employed in the making of these compounds such as

ethyl 2-(2-chloropyrid-5-yl)acetate;

ethyl 5-(2-chloropyrid-5-yl)pentanoate;

ethyl 2-(2-iodofur-5-yl)acetate;

ethyl 5-(2-iodofur-5-yl)pentanoate;

ethyl 2-(2-iodothien-5-yl)acetate;

ethyl 5-(2-iodothien-5-yl)pentanoate;

ethyl 2-(3-chloropyridazin-6-yl)acetate;

ethyl 5-(3-chloropyridazin-6-yl)pentanoate; and the correspondingchloro, or other halo, substituted pyrimidinyl or pyrazinyl analogues ofsuch esters.

EXAMPLE 6 Ethyl 6-[2-(4,4-dunethylthiochroman-6-yl)ethynyl]nicotinate

Reaction vessels used in this procedure were flame dried under vacuumand all operations carried out in an oxygen-free, argon or nitrogenatmosphere. To a solution of 465.7 mg (2.3019 mmol) of4,4-dimethyl-6-ethynyl-thiochroman in 4 ml of dry tetrahydrofuran at 0°C. was added dropwise 1.5 ml of 1.6M (2.4 mmol) n-butyllithium inhexane. This was stirred at 0° C. for 10 minutes and at room temperaturefor 10 minutes, cooled again to 0° C. and then treated with a solutionof 330 mg (2.4215 mmol) of fused ZnCl₂ in 4 ml dry tetrahydrofuran usinga double ended needle. Thereafter the solution was stirred at 0° C. for30 minutes, then at room temperature for 10 minutes. A solution of 426.3mg (2.2967 mmol) of ethyl 6-chloronicotinoate (from Example 5) in 4 mldry tetrahydrofuran was transferred by double ended needle into asuspension of 430 mg (0.37 mmol) of tetrakistriphenylphosphine palladiumin 4 ml dry tetrahydrofuran and stirred at room temperature for 10minutes, then treated by double ended needle with the solution of thealkynylzinc prepared above. This mixture was stirred at room temperaturefor 18 hours, then quenched with 100 ml water. Product was recovered byextraction with 3×75 ml ether. Ether fractions were combined and washedwith saturated NaCl solutions and dried (mgSO₄). Solvent was removed invacuo and the residue purified by flash chromatography (silica; 5% ethylacetate in hexane) followed by HPLC (Whatman Partisil M-9 10/50; 4%ethyl acetate in hexane) to give the title compound as a white solid.

PMR (CDCl₃): δ 1.36 (6H, s), 1.45 (3H, t, J˜7 Hz), 1.96-2.00 (2H, m),3.05-3.09 (2H, m), 4.45 (2H, q, J˜7 Hz), 7.11 (1H, d, J˜8.4 Hz), 7.29(1H, dd, J˜8.4 Hz, 2.2 Hz), 7.59 (1H, d, J˜7.8 Hz), 7.66 (1H, d, J˜2.2Hz), 8.30 (1H, dd, J˜7.8 Hz, 2.3 Hz), 9.22 (1H, d, J˜2.3 Hz).

Using this method, but substituting the appropriate ethynylthiochromanfrom Example 4 and the appropriate halo-substituted heteroaromatic esterfrom Example 5, the following compounds may be prepared:

ethyl 6-(2(4,4,7-trimethylthiochroman-6-yl)-ethynyl)nicotinate;

ethyl 6-(2-4,4-dimethyl-7-ethylthiochroman-6-yl)-ethynyl)nicotinate;

ethyl 6-(2-(4,4-dimethyl-7-propylthiochroman-6-yl)ethynyl)nicotinate;

ethyl 6-(2-(4,4-dimethyl-7-hexylthiochroman-6-yl)ethynyl)nicotinate;

ethyl (2-((4,4-dimethylthiochroman-6-yl)ethynyl)pyrid-5-yl)acetate;

ethyl (2-((4,4,7-trimethylthiochroman-6-yl)ethynyl)pyrid-5-yl)acetate;

ethyl(2-((4,4-dimethyl-7-ethylthiochroman-6-yl)ethynyl)pyrid-5-yl)acetate;

ethyl(2-((4,4-dimethyl-7-hexylthiochroman-6-yl)ethynyl)pyrid-5-yl)acetate;

ethyl 3-(2-((4,4-dimethylthiochrom-2-yl)ethynyl)pyrid-5-yl)propionate;

ethyl3-(2-((4,4,7-trimethylthiochroman-6-yl)ethynyl)pyrid-5-yl)propionate;

ethyl3-(2((4,4-dimethyl-7-ethylthiochroman-6-yl)ethynyl)pyrid-5-yl)propionate;

ethyl3-(2((4,4-dimethyl-7-hexylthiochroman-6-yl)-ethynyl)pyrid-5-yl)propionate;

ethyl 5-(2-((4,4-dimethylthiochroman-6-yl)ethynyl)pyrid-5-yl)pentanoate;

ethyl5-(2-((4,4,7-trimethylthiochroman-6-yl)ethynyl)pyrid-5-yl)pentanoate;

ethyl5-(2-((4,4-dimethyl-7-ethylthiochroman-6-yl)ethynyl)pyrid-5-yl)pentanoate;

ethyl (5-((4,4-dimethylthiochroman-6-yl)ethynyl)fur-2-yl)acetate;

ethyl (5-((4,4,7-trimethylthiochroman-6-yl)ethynyl)fur-2-yl)acetate;

ethyl(5-((4,4-dimethyl-7-ethylthiochroman-6-yl)ethynyl)fur-2-yl)acetate;

ethyl(5-((4,4-dimethyl-7-hexylthiochroman-6-yl)ethynyl)fur-2-yl)acetate;

ethyl 5-(5-((4,4-dimethylthiochroman-6-yl)ethynyl)fur-2-yl)pentanoate;

ethyl5-(5-((4,4,7-trimethylthiochroman-6-yl)ethynyl)fur-2-yl)pentanoate;

ethyl5-(5-((4,4-dimethyl-7-ethylthiochroman-6-yl)ethynyl)fur-2-yl)pentanoate;

ethyl5-(5-((4,4-dimethyl-7-hexylthiochroman-6-yl)ethynyl)fur-2-yl)pentanoate;

ethyl (5-((4,4-dimethylthiochroman-6-yl)ethynyl)thien-2-yl)acetate;

ethyl (5-((4,4,7-trimethylthiochroman-6-yl)ethynyl)thien-2-yl)acetate;

ethyl(5-((4,4-dimethyl-7-ethylthiochroman-6-yl)ethynyl)thien-2-yl)acetate;

ethyl(5-((4,4-dimethyl-7-hexylthiochroman-6-yl)ethynyl)thien-2-yl)acetate;

ethyl 5-(5-((4,4-dimethylthiochroman-6-yl)ethynyl)thien-2-yl)pentanoate;

ethyl5-(5-((4,4,7-trimethylthiochroman-6-yl)ethynyl)thien-2-yl)pentanoate;

ethyl5-(5-((4,4-dimethyl-7-ethylthiochroman-6-yl)ethynyl)thien-2-yl)pentanoate;

ethyl5-(5-((4,4-dimethyl-7-hexylthiochroman-6-yl)ethynyl)thien-2-yl)pentanoate;

ethyl (6-((4,4-dimethylthiochroman-6-yl)ethynyl)pyridazin-3-yl)acetate;

ethyl (6-((4,4,7-trimethylthiochroman-6-yl)ethynyl)pyridazin-3-yl)acetate;

ethyl(6-((4,4-dimethyl-7-ethylthiochroman-6-yl)ethynyl)pyridazin-3-yl)acetate;

ethyl(6-((4,4-dimethyl-7-hexylthiochroman-6-yl)ethynyl)pyridazin-3-yl)acetate;

ethyl5-(6-((4,4-dimethylthiochroman-6-yl)ethynyl)pyridazin-3-yl)pentanoate;

ethyl5-(6-((4,4,7-trimethylthiochroman-6-yl)ethynyl)pyridazin-3-yl)pentanoate;

ethyl5-(6-((4,4-dimethyl-7-ethylthiochroman-6-yl)ethynyl)pyridazin-3-yl)pentanoate;

ethyl5-(6-((4,4-dimethyl-7-hexylthiochroman-6-yl)ethynyl)pyridazin-3-yl)pentanoate;

ethyl (5-((4,4-dimethylthiochroman-6-yl)ethynyl)pyrimidin-2-yl)acetate;

ethyl(5-((4,4,7-trimethylthiochroman-6-yl)ethynyl)pyrimidin-2-yl)acetate;

ethyl(5-((4,4-dimethyl-7-ethylthiochroman-6-yl)ethynyl)pyrimidin-2-yl)acetate;

ethyl(5-((4,4-dimethyl-7-hexylthiochroman-6-yl)ethynyl)pyrimidin-2-yl)acetate;

ethyl5-(5-((4,4-dimethylthiochroman-6-yl)ethynyl)pyrimidin-2-yl)pentanoate;

ethyl5-(5-((4,4,7-trimethylthiochroman-6-yl)ethynyl)pyrimidin-2-yl)pentanoate;

ethyl5-(5-((4,4-dimethyl-7-ethylthiochroman-6-yl)ethynyl)pyrimidin-2-yl)pentanoate;

ethyl5-(5-((4,4-dimethyl-7-hexylthiochroman-6-yl)ethynyl)pyrimidin-2-yl)pentanoate;

ethyl (5-((4,4-dimethylthiochroman-6-yl)ethynyl)pyrazin-2-yl )acetate;

ethyl (5-((4,4,7-trimethylthiochroman-6-yl)ethynyl)pyrazin-2-yl)acetate;

ethyl(5-((4,4-dimethyl-7-ethylthiochroman-6-yl)ethynyl)pyrazin-2-yl)acetate;

ethyl(5-((4,4-dimethyl-7-hexylthiochroman-6-yl)ethynyl)pyrazin-2-yl)acetate;

ethyl5)5-((4,4-dimethylthiochroman-6-yl)ethynyl)pyrazin-2-yl)pentanoate;

ethyl5-(5-((4,4,7-trimethylthiochroman-6-yl)ethynyl)pyrazin-2-yl)pentanoate;

ethyl5-(5-((4,4-dimethyl-7-ethylthiochroman-6-yl)ethynyl)pyrazin-2-yl)pentanoate;and

ethyl5-(5-((4,4-dimethyl-7-hexylthiochroman-6-yl)ethynyl)pyrazin-2-yl)pentanoate.

Alternative synthesis: The title compound of Example 6, ethyl6-[2-(4,4-dimethylthiochroman-6-yl)ethynyl]nicotinate, was also preparedas follows.

A solution of 15.4 g (76.2 mmol) of 4,4-dimethyl-6-ethynylthiochromanand 14.0 g (75.5 mmol) of ethyl-6-chloronicotinate in 35 ml of freshlydistilled triethylamine was degassed and then treated under nitrogenwith a finely powdered mixture of 1 g (5.25 mmol) of high purity cuprousiodide and 2 g (2.85 mmol) of bis(triphenylphosphine) palladium (II)chloride. The mixture was heated under nitrogen at 55° C. for 20 hoursand then cooled to room temperature. The triethylamine was then removedunder vacuum and the residue was diluted with 200 ml of a 1:4 mixture ofethyl acetate and hexanes. This mixture was filtered through silica andthe filtrate concentrated in vacuo. The resultant residue was purifiedby flash chromatography (silica gel; 15% ethyl acetate in hexanes) andrecrystallized from a mixture of ethyl acetate and hexanes to give thetitle compound as a pale yellow solid.

EXAMPLE 7 (3-Methyl-4-bromo-phenyl)-3-methylbut-2-enylsulfide

To a stirred solution of 9.52 g (68 mmol) of 3-methyl-4-bromothiophenolin 80 ml of acetone was added 2.86 g (68 mmol) of powdered sodiumhydroxide. This mixture was stirred until the components were dissolved.The reaction mixture was then heated to reflux, and then treated with asolution of 11.26 g (68 mmol) of 4-bromo-2-methyl-2-butene in 20 ml ofacetone. The mixture was heated at reflux for a further 0.5 hour, cooledto room temperature and the solvent removed in vacuo. The residue wastaken up in 35 ml of water and extracted with ether. The ether extractswere combined and washed successively with water and saturated NaClsolution and then dried (MgSO₄). The solvent was removed in vacuo andthe residue kugelrohr distilled (140°-145° C., 0.2 mm) to give the titlecompound as a colorless oil.

PMR (CDCl₃): δ 1.58 (3H, s), 1.70 (3H, s), 2.33 (3H, s), 3.49 (2H, d,J˜7.8 Hz), 5.26 (1H, t, J˜7.8 Hz), 6.98 (1H, rid, J˜8.3 Hz, 2.3 Hz),7.17 (1H, d J˜2.3 Hz), 7.38 (1H d, J˜8.3 Hz).

EXAMPLE 8 4,4,7-Trimethyl-6-bromothiochroman

To 40 g of a vigorously stirred mixture of 10% phosphorous pentoxide inmethanesulfonic acid was added slowly 6.0 g (28.8 mmol) of(3-methyl-4-bromophenyl)-3-methylbut-2-enylsulfide. The mixture wasstirred at room temperature for a further 2 hours and was then pouredonto ice. The mixture was extracted with 2×40 ml of ether and thecombined ether extracts were washed successively with water andsaturated NaCl solution and then dried. The solvent was removed in vacuoand the residue distilled using a kugelrohr apparatus (130° C.; 0.07 mm)to give the title compound as a viscous oil.

PMR (CDCl₃): δ 1.28 (6H, s) 1.84-1.93 (2H, m), 2.26 (3H, s), 2.95-3.03(2H, m), 6.94 (1H, s), 7.46 (1H, s).

EXAMPLE 9 4,4,7-Trimethyl-6-trimethylsilylethynylthiochroman

A mixture of 624 mg (3.0 mmol) of 4,4,7-trimethyl-6-bromothiochroman,314 mg (3.2 mmol) of trimethylsilylacetylene, 40 mg (0.21 mmol) ofcuprous iodide, 80 mg (0.11 mmol) of bis-(triphenylphosphine) palladium(II) chloride and 1 ml of triethylamine was degassed under nitrogen andheated in a scaled tube at 85° C. for 15 hours. The mixture was thentreated with a further 20 mg (0.11 mmol) of cuprous iodide and 40 mg(0.06 mmol) of the palladium (II) catalyst. The mixture was then heatedunder a nitrogen atmosphere in the sealed tube at 100° C. for a further64 hours. The triethylamine was then removed under vacuum and theresidue purified by flash chromatography (silica; hexanes) to give thetitle compound as a yellow oil.

PMR(CDCl₃): δ 0.28 (9H, s), 1.30 (6H, s), 1.88-1.97 (2H, m), 2.33 (3H,s), 2.97-3.05 (2H, m), 6.92 (1H, s), 7.43 (1H, s).

EXAMPLE 10 4,4,7-Trimethyl-6-ethynylthiochroman

A mixture of 380 mg (1.69 mmol) of4.4.7-trimethy-6-trimethylsilylethynylthiochroman, 4 ml of isopropanoland 2.5 ml of aqueous 1N potassium hydroxide was degassed under nitrogenand stirred at room temperature for 16 hours. The mixture wasconcentrated under vacuum and extracted with 2×10 ml of ether. The etherextracts were combined and washed successively with water and saturatedNaCl solution and then dried (MgSO₄). The solvent was removed in vacuoto give the title compound as a yellow oil.

PMR (CDCl₃): δ 1.31 (6H, s), 1.88-1.96 (2H, m), 2.35 (3H, s), 3.00-3.08(2H, m), 3.2.5 (1H s), 6.94 (1H, s), 7.47 (1H s).

EXAMPLE 11 Ethyl6-[2-(4,4,7-trimethylthiochroman-6-yl)ethynyl]nicotinate

A mixture of 86 mg (0.4 mmol) of 4,4,7-trimethyl-6-ethynylthiochroman,85 mg (0.46 mmol) of ethyl 6-chloronicotinate and 0.8 ml oftriethylamine was degassed under nitrogen and then treated with amixture of 10 mg (0.05 mmol) of cuprous iodide and 20 mg (0.03 mmol) ofbis(triphenylphosphine) palladium (II) chloride. The reaction mixturewas heated at 55° C. under a nitrogen atmosphere for 18 hours. Themixture was then extracted with 1.5 ml of 40% ethyl acetate in hexanesand purified by flash chromatography (silica; 10% ethyl acetate inhexanes) to give the title compound as a yellow solid.

PMR (CDCl₃): δ 1.32 (6H, s), 1.43 (3H, t, J˜7.2 Hz), 2.44 (3H, s),3.01-3.05 (2H, m), 4.42 (2H, q, J˜7.2 Hz), 6.98 (1H, s), 7.54-7.63 (2H,m), 8.27 (1H, dd, J˜8.3 Hz, 2.3 Hz), 9.21 (1H, d, J˜2.3 Hz).

EXAMPLE 12 Ethyl5-(2-(4,4-dimethyl-thiochroman-6-yl)ethynyl)thiophene-2-carboxylate

Using the same general procedure described in the preceeding Example 11,but using instead 4,4-dimethyl-6-ethynylthiochroman and ethyl5-bromothiophene-2-carboxylate, the title compound was synthesized.

PMR (CDCl₃): δ 1.31 (6H, s), 1.36 (3H, t, J˜7.5 Hz), 1.90-1.94 (2H, m),2.99-3.03 (2H, m), 4.33 (2H, q, J˜7.5 Hz), 7.04 (1H, d, J˜8.1 Hz),7.13-7.18 (2H, m), 7.50 (1H s), 7.65 (1H, d, J˜3.9 Hz).

EXAMPLE 13 Ethyl-5-(2-(4,4-dimethylthiochroman-6-yl)ethynyl)-2-furoate

Again using the general procedure of Example 11, but using instead4,4-dimethyl-6-ethynylthiochroman and ethyl 5-bromo-2-furate, the titlecompound was synthesized.

PMR (CDCl₃): δ 1.24 (6H, s), 1.31 (3H, t, J˜7.0 Hz), 1.83-1.87 (2H, m),2.93-2.97 (2H, m), 4.30 (2H, q, J˜7.0 Hz), 6.60 (1H, d, J˜3.4 Hz), 6.98(1H, d, J˜8.1 Hz), 7.09-7.11 (2H, m), 7.46 (1H, d, J˜1.7 Hz).

EXAMPLE 14 Diphenyl-3-methyl-3-buten-1-yl phosphate

To an ice-cooled solution of 12.2 g (141.65 mmol) of3-methyl-3-buten-1-ol (Aldrich) and 11.9 g (150.44 mmol) of pyridine in100 ml of tetrahydrofuran was added dropwise under argon a solution of38.5 g (143.21 mmol) Of diphenyl chlorophosphate 93 in 100 ml oftetrahydrofuran. The mixture was heated at reflux for 3 hours and thencooled and filtered. The filtrate was concentrated in vacuo and theresidue dissolved in 400 ml of 1:1 ether and hexane and then washed with2×200 ml water, 75 ml saturated NaCl solution and dried (MgSO₄). Thesolvent was removed in vacuo to give the captioned compound as a paleyellow oil.

PMR (CDCl₃): δ 1.69 (3H, M), 2.37 (2H, t, J N7 Hz), 4.32 (2H, q, J˜7Hz), 4.72 (1H, M), 7.10-7.35 (10H, m).

EXAMPLE 15 4,4-Dimethylchroman

To a dry, ice-cooled flask containing 34.95 g (0.134 mol) of stannicchloride was added quickly under argon 63.0 g (0.669 mol) of phenol. Themixture was stirred at 0° C. for 0.5 hour and then treated with 43.0 g(0.135 mol) of diphenyl-3-methyl-3-buten-1-yl phosphate, followed by a 5ml carbon disulfide rinse. The mixture was stirred at room temperaturefor 21 hours and then quenched by pouring onto 700 g ice and 1 liter of1.5N NaOH. The mixture was extracted with 1×600 ml and 2×300 ml ether.The combined ether fractions were washed with 2N NaOH, saturated NaCland dried (MgSO₄). Solvent was removed in vacuo and the residue purifiedby flash chromatography (silica; 2% ether in hexane) to give the titlecompound as a colorless oil.

PMR (CDCl₃): δ 1.34 (6H, M), 1.80-1.85 (2H, m), 4.15-4.20 (2H, m), 6.80(1H, dd, J˜8.1 Hz, 1.5 Hz), 6.87 (1H d, J˜8.1 Hz, 1.5 Hz), 7.07 (1H, td,J˜8.1 Hz, 1.5 Hz), 7.26 (1H, dd, J˜8.1 Hz, 1.5 Hz).

This method also serves to prepare the corresponding 7-alkylchromancompounds, starting with the appropriate 3-alkylphenol, for example:

4,4,7-trimethylchroman;

4,4-dimethyl-7-ethylchroman;

4,4-dimethyl-7-propylchroman;

4,4-dimethyl-7-butylchroman;

4,4-dimethyl-7-pentylchroman; and

4,4-dimethy-7-hexylchroman.

EXAMPLE 16 4,4-Dimethyl-6-acetylchroman

To a stirred solution of 7.94 g (48.9425 mmol) of 4,4-dimethylchroman in70 ml of nitromethane was added under argon 4.0 g (50.96 mmol) of acetylchloride followed by 6.8 g (51 mmol) of aluminum chloride. This wasstirred at room temperature for 5.5 hours and then cooled in an ice bathand treated slowly with 70 ml 6N hydrogen chloride. The resultantmixture was stirred at room temperature for 10 minutes, then treatedwith 100 ml ether and the organic layer separated. The organic layer waswashed with water, saturated NaHCO₃ and saturated NaCl solutions anddried (MgSO₄). Solvent was removed in vacuo and the residue purified byflash chromatography (silica; 10% ethyl acetate in hexanes). This wasfollowed by kugelrohr distillation (95°-100° C.; 0.15 mm) to give thetitle compound as a colorless oil.

PMR (CDCl₃): δ 1.40 (6H, M), 1.95-2.00 (2H, m), 2.58 (3H, M), 4.25-4.30(2H, m), 6.83 (1H, d, J˜8.0 Hz), 7.62 (1H, rid, J˜8.0 Hz, 1.5 Hz), 8.00(1H, d, J˜1.5 Hz).

Following the same procedure and using the compounds of Example 15, thefollowing compounds can be prepared:

4,4-dimethyl-6-acetyl-7-methylchroman;

4,4-dimethyl-6-acetyl-7-ethylchroman;

4,4-dimethyl-6-acetyl-7-propylchroman;

4,4-dimethyl-6-acetyl-7-butylchroman;

4,4-dimethyl-6-acetyl-7-pentylchroman; and

4,4-dimethyl-6-acetyl-7-hexylchroman.

EXAMPLE 17 4,4-Dimethyl-6-ethynylchroman

To a solution of 2.47 g (24.41 mmol) of diisopropylamine in 40 ml drytetrahydrofuran under argon at -78° C. was added dropwise 15.2 ml of1.6M (24.32 mmol) n-butyl lithium in hexane. Mixture was stirred at -78°C. for 1 hour and then treated dropwise with a solution of 4.98 g (24.38mmol) of 4,4-dimethyl-6-acetylchroman in 4 ml of dry tetrahydrofuran.After stirring at -78° C. for 1 hour, the solution was treated with 4.2g (24.36 mmol) of diethyl chlorophosphate. The cooling bath was thenremoved and mixture stirred at room as temperature for 2.75 hours. Thissolution was then transferred using a double ended needle to a solutionof lithium diisopropyl amide (prepared as per Example 4) using 4.95 g(48.92 mmol) of diisopropylamine and 30.5 ml of 1.6M (48.8 mmol) n-butyllithium in hexane in 80 ml dry tetrahydrofuran at -78° C. The coolingbath was removed and mixture stirred at room temperature for 18 hoursand then quenched with 50 ml water and 25 ml of 3N hydrogen chloride.The mixture was extracted with 2×100 ml and 3×50 ml of pentane and thecombined organic fractions washed with 3N hydrogen chloride, water,saturated NaHCO₃ and saturated NaCl solution and then dried (MgSO₄).Solvent was then removed in vacuo and the residue purified by flashchromatography (silica; 10% ethyl acetate in hexane) followed bykugelrohr distillation (70° C.; 0.35 mm) to give the title compound as acolorless crystalline solid.

PMR (CDCl₃): δ 1.33 (6H, s), 1.81-1.86 (2H, m), 3.00 (1H, s), 4.19-4.24(2H, m), 6.75 (1H, d, J˜8.5 Hz), 7.22 (1H, dd, J˜8.5 Hz, 2.3 Hz), 7.44(1H d, J˜2.3 Hz).

This procedure serves to convert all acetyl-containing compoundsprepared as per Example 16 to their corresponding ethynyl-containingcompounds.

EXAMPLE 18 Ethyl 6-[2-(4,4-dimethylchroman-6-yl)ethynyl]nicotinate

Reaction vessels used in this procedure were flame dried under vacuumand all operations were carried out in an oxygen-free, argon or nitrogenatmosphere. To a solution of 509.4 mg (2.74 mmol) of4,4-dimethyl-6-ethynylchroman in a ml of dry tetrahydrofuran at 0° C.was added dropwise 1.72 ml of 1.6M (2.75 mmol) of n-butyl lithium inhexane. Stirring was commenced at 0° C. for 30 minutes and at roomtemperature for 15 minutes, after which the solution was cooled again to0° C. and then treated with a solution of 380 mg (2.79 mmol) of fusedzinc chloride in 5 ml of dry tetrahydrofuran using a double endedneedle. The resulting solution was stirred at 0° C. for 1 hour and thenat room temperature for 15 minutes. A solution of 628.6 mg (2.74 mmol)of ethyl 6-chloronicotinate in 4 ml of dry tetrahydrofuran wastransferred by double ended needle into a suspension of 380 mg (0.33mmol) of tetrakistriphenylphosphine palladium in 5 ml drytetrahydrofuran and mixture stirred at room temperature for 15 minutesand then treated by double ended needle with the solution of alkynylzincprepared above. The mixture was stirred at room temperature for 20 hoursand then quenched with ice and 30 ml of 3N hydrogen chloride. Themixture was extracted with 3×75 ml ether and ether extracts werecombined and washed successively with saturated NaHCO₃ and saturatedNaCl and then dried (MgSO₄). Solvent was removed in vacuo and theresidue further purified by flash chromatography (silica; 10% ethylacetate in hexane) to give the title compound as a yellow solid.

PMR (CDCl₃): δ 1.36 (6H, s), 1.44 (3H, t, J˜7.1 Hz), 1.83-1.87 (2H, m),4.22-4.26 (2H, m), 4.44 (2H, q, J˜7.1 Hz), 6.80 (1H, d, J˜7.6 Hz), 7.35(1H, d, J˜8.9 Hz), 7.58 (1H, d, J˜7.6 Hz), 7.60 (1H, M), 8.28 (1H, d,J˜8.9 Hz), 9.21 (1H, s).

By this method, using the appropriate precursors, the followingcompounds are prepared:

ethyl 6-(2(4,4,7-trimethylchroman-6-yl)-ethynyl)nicotinate;

ethyl 6-(2-(4,4-dimethyl-7-ethylchroman-6-yl)ethynyl)nicotinate;

ethyl 6-(2-(4,4-dimethyl-7-propylchroman-6-yl)ethynyl)nicotinate;

ethyl 6-(2-(4,4-dimethyl-7-hexylchroman-6-yl)ethynyl)nicotinate;

ethyl (2-((4,4-dimethylchroman-6-yl)ethynyl)pyrid-5-yl)acetate;

ethyl (2-((4,4,7-trimethylchroman-6-yl)ethynyl)pyrid-5-yl)acetate;

ethyl (2-((4,4-dimethyl-7-ethylchroman-6-yl)ethynyl)pyrid-5-yl)acetate;

ethyl (2-((4,4-dimethyl-7-hexylchroman-6-yl)ethynyl)pyrid-5-yl)acetate;

ethyl 3-(2-((4,4-dimethylchroman-2-yl)ethynyl)pyrid-5-yl)propionate;

ethyl 3-(2-((4,4,7-trimethylchroman-6-yl)-ethynyl)pyrid-5-yl)propionate;

ethyl3-(2((4.4-dimethyl-7-ethylchroman-6-yl)-ethynyl)pyrid-5-yl)propionate;

ethyl3-(2((4,4-dimethyl-7-hexylchroman-6-yl)-ethynyl)pyrid-5-yl)propionate;

ethyl 5-(2-((4,4-dimethylchroman-6-yl)ethynyl)pyrid-5-yl)pentanoate;

ethyl 5-(2-((4,4,7-trimethylchroman-6-yl)ethynyl)pyrid-5-yl)pentanoate;

ethyl5-(2-((4,4-dimethyl-7-ethylchroman-6-yl)ethynyl)pyrid-5-yl)pentanoate;

ethyl5-(2-(4,4-dimethyl-7-hexylchroman-6-yl-ethynyl)pyrid-5-yl)pentanoate;

ethyl 5-(2-((4,4-dimethylchroman-6-yl)ethynyl)fur-2-yl)acetate;

ethyl (5-((4,4,7-trimethylchroman-6-yl)ethynyl)fur-2-yl)acetate;

ethyl (5-((4,4-dimethyl-7-ethylchroman-6-yl)ethynyl)fur-2-yl)acetate;

ethyl (5-((4,4-dimethyl-7-hexylchroman-6-yl)ethynyl)fur-2-yl)acetate;

ethyl 5-(5-((4,4-dimethylchroman-6-yl)ethynyl)fur-2-yl)pentanoate;

ethyl 5-(5-((4,4,7-trimethylchroman-6-yl)ethynyl)fur-2-yl)pentanoate;

ethyl5-(5-((4,4-dimethyl-7-ethylchroman-6-yl)ethynyl)fur-2-yl)pentanoate;

ethyl5-(5-((4,4-dimethyl-7-hexylchroman-6-yl)ethynyl)fur-2-yl)pentanoate;

ethyl (5-((4,4-dimethylchroman-6-yl)ethynyl)thien- 2-yl)acetate;

ethyl (5-((4,4,7-trimethylchroman-6-yl)ethynyl)thien-2-yl)acetate;

ethyl (5-((4,4-dimethyl-7-ethylchroman-6-yl)ethynyl)thien-2-yl)acetate;

ethyl (5-((4,4-dimethyl-7-hexylchroman-6-yl)ethynyl)thien-2-yl)acetate;

ethyl 5-(5-((4,4-dimethylchroman-6-yl)ethynyl)thien-2-yl)pentanoate;

ethyl 5-(5-((4,4,7-trimethylchroman-6-yl)-ethynyl)thien-2-yl)pentanoate;

ethyl5-(5-((4,4-dimethyl-7-ethylchroman-6-yl)ethynyl)thien-2-yl)pentanoate;

ethyl5-(5-((4,4-dimethyl-7-hexylchroman-6-yl)ethynyl)thien-2-yl)pentanoate;

ethyl (6-((4,4-dimethylchroman-6-yl)ethynyl)pyridazin-3-yl)acetate;

ethyl (6-((4,4,7-trimethylchroman-6-yl)ethynyl)pyridazin-3-yl)acetate;

ethyl(6-((4,4-dimethyl-7-ethylchroman-6-yl)ethynyl)pyridazin-3-yl)acetate;

ethyl(6-((4,4-dimethyl-7-hexylchroman-6-yl)ethynyl)pyridazin-3-yl)acetate;

ethyl 5-(6-((4,4-dimethylchroman-6-yl)ethynyl)pyridazin-3-yl)pentanoate;

ethyl5-(6-((4,4,7-trimethylchroman-6-yl)-ethynyl)pyridazin-3-yl)pentanoate;

ethyl5-(6-((4,4-dimethyl-7-ethylchroman-6-yl)ethynyl)pyridazin-3-yl)pentanoate;

ethyl5-(6-((4,4-dimethyl-7-hexylchroman-6-yl)ethynyl)pyridazin-3-yl)pentanoate;

ethyl (5-((4,4-dimethylchroman-6-yl)ethynyl)pyrimidin-2-yl )acetate;

ethyl (5-((4,4,7-trimethylchroman-6-yl)ethynyl)pyrimidin-2-yl )acetate;

ethyl(5-((4,4-dimethyl-7-ethylchroman-6-yl)ethynyl)pyrimidin-2-yl)acetate;

ethyl(5-((4,4-dimethyl-7-hexylchroman-6-yl)ethynyl)pyrimidin-2-yl)acetate;

ethyl 5-(5-((4,4-dimethylchroman-6-yl)ethynyl)pyrimidin-2-yl)pentanoate;

ethyl5-(5-((4,4,7-trimethylchroman-6-yl)-ethynyl)pyrimidin-2-yl)pentanoate;

ethyl5-(5-((4,4-dimethyl-7-ethylchroman-6-yl)ethynyl)pyrimidin-2-yl)pentanoate;

ethyl5-(5-((4,4-dimethyl-7-hexylchroman-6-yl)ethynyl)pyrimidin-2-yl)pentanoate;

ethyl (5-((4,4-dimethylchroman-6-yl)ethynyl)pyrazin-2-yl)acetate;

ethyl (5-((4,4,7-trimethylchroman-6-yl)ethynyl)pyrazin-2-yl)acetate;

ethyl(5-((4,4-dimethyl-7-ethylchroman-6-yl)ethynyl)pyrazin-2-yl)acetate;

ethyl(5-((4,4-dimethyl-7-hexylchroman-6-yl)ethynyl)pyrazin-2-yl)acetate;

ethyl 5)(5-((4,4-dimethylchroman-6-yl)ethynyl)pyrazin-2-yl)pentanoate;

ethyl5-(5-((4,4,7-trimethylchroman-6-yl)-ethynyl)pyrazin-2-yl)pentanoate;

ethyl5-(5-((4,4-dimethyl-7-ethylchroman-6-yl)ethynyl)pyrazin-2-yl)pentanoate;and

ethyl 5-(5-((4,4-dimethyl-7-hexylchroman-6-yl)ethynyl)pyrazin-2-yl)pentanoate.

EXAMPLE 19 N-(4-Bromophenyl)-3,3-dimethylarylamide

To a solution of 9.48 g (80 mmol) of 3,3-dimethylacryloyl chloride in200 ml of dry tetrahydrofuran (THF) was added with vigorous shaking asolution of 13.76 g (80 mmol) of 4-bromoaniline in 300 ml of dry THF.The mixture stood at room temperature for 2 hours and was then treatedwith 80 g of ice followed by 200 ml of hexane. The organic layer wasseparated and the aqueous layer was extracted with 2×50 ml of hexanes.The organic layers were combined and washed successively with 30 ml ofwater and 2×30 ml of saturated NaCl solution and then dried (MgSO₄). Thesolvent was removed in vacuo and the residue purified byrecrystallization from an ethyl acetate and hexanes mixture to give thetitle compound as colorless crystals.

PMR (CDCl₃): δ 1.91 (3H, s), 2.23 (3H, s), 5.73 (1H, broad s), 7.38-7.55(5H, m).

EXAMPLE 20 4,4-Dimethyl-6-bromo-2-oxo-1,2,3,4-tetrahydroquinoline

To 6.7 g (26.02 mmol) of molten N-(4-bromophenyl)3,3-dimethylacrylamide(heated to 135° C.) was added 4.15 g (31.09) of aluminum chloride over25 minutes. The reaction mixture was stirred at 130° C. for 16 hours andthen treated with a further 1 g of aluminum chloride. The reactionmixture was heated at 130° C. for a further 9 hours and then cooled toroom temperature. The reaction was then quenched by the slow addition of100 ml of ice cold water with slight warming of flask to facilitatemixing. The mixture was extracted with 1×100 ml and 4×50 ml of ether.The organic extracts were combined and washed with 25 ml of saturatedNaCl solution and then dried (MgSO₄). The solvent was removed in vacuoand the residue purified by flash chromatography (silica; 30% ethylacetate in hexanes) to give the title compound as a pale yellow solid.

PMR (CDCl₃): δ 1.37 (6H, s), 2.53 (2H, s), 6.85 (1H, d, J˜8.4 Hz), 7.32(1H, dd, J˜8.4 Hz, 2.1 Hz), 7.43 (1H, d, J˜2.1 Hz), 10.12 (1H, broad S).

EXAMPLE 21 4,4-Dimethyl-6-bromo-1,2,3,4-tetrahydroquinoline

To 23.5 ml of 1.0M (23.5 mmol) lithium aluminum hydride in THF, heatedto reflux under nitrogen, was added a solution of 4.95 g (19.48 mmol) of4,4-dimethyl-6-bromo-2-oxo-1,2,3,4-tetrahydroquinoline in 50 ml of dryTHF and 100 ml of dry diethyl ether via a double-ended needle. Themixture was heated at reflux for 2 hours and then cooled to roomtemperature. The reaction mixture was then quenched by the slow additionof 25 ml of water followed by 50 ml of 5% NaOH solution. The mixture wasextracted with 2×25 ml of ether, the organic extracts were combined andwashed successively with 25 ml each of water and saturated NaCl solutionand then dried (MgSO₄). The solvent was removed in vacuo and the residuepurified by flash chromatography (silica; 15% ethyl acetate in hexanes)to give the title compound as a brown oil.

PMR (CDCl₃): δ 1.27 (6H, s), 1.67-1.74 (2H, m), 3.23-3.32 (2H, m), 3.90(1H, broad s), 6.33 (1H, d, J˜8.4 Hz), 7.10 (1H, dd, J˜8.4 Hz, 2.3 Hz),7.25 (1H, d, J˜2.3 Hz).

EXAMPLE 224,4-Dimethyl-6-trimethylsilylethynyl-1,2,3,4-tetrahydroquinoline

A solution of 1.608 g (6.7 mmol) of4,4-dimethyl-6-bromo-1,2,3,4-tetrahydroquinoline in 1.5 ml oftriethylamine in a heavy-walled tube was degassed under argon and thentreated with 75 mg (0.39 mmol) of cuprous iodide and 150 mg (0.21 mmol)of bis(triphenylphosphine) palladium (II) chloride. The mixture wasdegassed again under argon, treated with 2.09 g (21.2 mmol) oftrimethylsilylacetylene and the tube was sealed. The mixture was heatedat 50° C. for 48 hours. After cooling to room temperature methylenechloride was added to the reaction mixture and the mixture filtered. Thefiltrate was concentrated in vacuo and the residue purified by flashchromatography (silica; 10% ethyl acetate in hexanes) to give the titlecompound as a yellow oil.

PMR (CDCl₃): δ 0.20 (9H, s), 1.20 (6H, s), 1.57-1.63 (2H, m), 3.16-3.25(2H, m), 4.02 (1H broad s), 6.24 (1H, d, J˜8.2 Hz), 7.00 (1H, dd, J˜8.2Hz, 1.8 Hz), 7.26 (1H, d, J˜1.8 Hz).

EXAMPLE 23 4,4-Dimethyl-6-ethynyl-1,2,3,4-tetrahydroquinoline

To a solution of 569 mg (2.21 mmol) of4,4-dimethyl-6-trimethylsilylethynyl-1,2,3,4-tetrahydroquinoline in 3 mlof isopropanol was added, under argon, 1 ml of 1N aqueous KOH solution.The reaction mixture was stirred at room temperature for 36 hours andthe isopropanol was removed under vacuum. The residue was extracted withether and the ether extract was washed successively with water andsaturated NaCl solution and then dried (MgSO₄). The solvent was removedin vacuo and the residue was purified by flash chromatography (silica;10% ethyl acetate in hexanes) to give the title compound as a brown oil.

PMR (CDCl₃): δ 1.26 (6H, s), 1.65-1.72 (2H, m), 2.96 (1H, s), 3.27-3.34(2H, m), 6.3 4 (1H, d, J˜8.3 Hz), 7.08 (1H, dd, J˜8.3 Hz, 1.6 Hz), 7.33(1H, d, J˜1.6 Hz).

EXAMPLE 24 6-(2-(4,4-dimethylchroman-6-yl)ethynyl)nicotinic acid

The absolute ethanol used in this experiment was degassed by applying avacuum while simultaneously bubbling nitrogen through it. A solution of101.1 mg (0.30 mmol) of ethyl6-(2-4,4-dimethylchroman-6-yl)ethylyl)-nicotinoate in 2 ml ethanol wastreated under argon with 0.7 ml of a 1.81M (1.27 mmol) solution ofpotassium hydroxide in ethanol and water. This mixture was stirred atroom temperature for 60 hours and then solvent removed in vacuo. Theresidue was dissolved in 25 ml of water and extracted with 25 ml ofether. The aqueous layer was acidified with glacial acetic acid andextracted with 4×50 ml of ether. Ether extracts were combined and washedwith water, then saturated NaCl and dried (MgSO₄). Solvent was thenremoved in vacuo to give the title compound. PMR ((CD₃)₂ CO): δ 1.40(6H, s) 1.88-1.92 (2H, m), 4.26-4.30 (2H, m), 6.82 (1H, d, J˜8.7 Hz),7.37 (1H, dd, J˜ 7.6 Hz, 2.2 Hz), 7.62 (1H, M), 7.63 (1H, d, J˜8.7 Hz),8.37 (1H, dd, J˜7.6 Hz, 2.2 Hz), 9.27 (1H, d, J˜2.2 Hz).

Proceeding in the same manner6-(2-(4,4-dimethylthiochroman-6-yl)ethynyl)nicotinic acid was preparedfrom ethyl 6-(2-(4,4-dimethylthiochroman-6-yl)-ethynyl)nicotinoate.

PMR (CDCl₃ (CD₃ )₂ CO): δ 1.37 (6H, M), 1.99 (2H, m), 3.09 (2H, m), 7.10(1H, d, J˜8.1 Hz), 7.28 (1H, dd J˜8.1 Hz), 2.1 Hz), 7.64 (1H, dd, J˜7.8Hz), 1.8 Hz), 7.65 (1H, d, J˜7.8 Hz, 1.5 Hz), 9.24 (1H, m).

Proceeding in the same manner, the esters prepared as per the preceedingExamples may be converted to their corresponding acid.

EXAMPLE 256-(2-(4,4-Dimethyl-thiochroman-6-yl)-ethynyl)-3-pyridylmethanol

To 3.0 ml of 1M lithium aluminum hydride (3.0 mmol) in THF, cooled to-78° C., was added dropwise over 5 min a solution of 2.0 g (5.9 mmol) ofethyl 6-(2-(4,4-dimethylthiochroman-6-yl)-ethynyl)nicotinate in 5 ml ofTHF. The reaction mixture was stirred at -78° C. for 40 rain and thentreated with 2 ml of water. The mixture was warmed to room temperatureand the organic layer was separated. The aqueous layer was extractedwith 3×10 ml of ether. The organic extracts were combined and washedsuccessively with 1×10 ml of dilute HCl, 3×10 ml of water and 1×15 ml ofsaturated NaCl solution and then dried (MgSO₄). The solvent was removedin vacuo and the residue purified by flash chromatography (silica; 50%ethyl acetate in hexanes) to give the title compound as a pale yellowsolid.

PMR (CDCl₃): δ 1.33 (6H, s), 1.91-1.98 (2H, m), 3.01-3.07 (2H, m), 4.75(2H, s), 7.08 (1H, d, J˜8.2 Hz), 7.23 (1H, dd, J˜8.2 Hz, 1.7 Hz), 7.46(1H, d, J˜7.9 Hz), 7.60 (1H, d, J˜1.2 Hz), 7.71 (1H, dd, J˜7.9 Hz, 1.2Hz), 8.51 (1H, broad s).

EXAMPLE 26 2-(4,4-dimethyl-thiochroman-6-yl)ethynyl)-5-bromopyridine

A mixture of 6.36 g (31.5 mmol) of 4,4-dimethyl-6-ethynylthiochroman,7.46 g (31.5 mmol) of 2,5-dibromopyridine, 122 mg (0.64 mmol) of cuprousiodide, 224 mg (0.32 mmol) of bis(triphenylphosphine) palladium (II)chloride and 70 ml of freshly distilled triethylamine was degassed undernitrogen and stirred at room temperature for 1 hour. The mixture wasthen treated with 180 ml of ether and 40 ml of water and the organiclayer was separated. The aqueous layer was extracted with ether, theorganic layers were combined and then washed with 2×40 ml of water, 2×40ml of saturated NaCl solution and then dried (K₂ CO₃). The solvent wasremoved in vacuo and the residue purified by flash chromatography(silica; 5% ethyl acetate in hexanes) and recrystallization from ethylacetate and hexane to give the title compound as a pale brown solid.

PMR (CDCl₃): δ 1.34 (6H, s), 1.94-1.98 (2H, m), 3.04-3.08 (2H, m), 7.08(1H, d, J˜8.4 Hz), 7.23 (1H, dd, J˜8.4 Hz, 1.8 Hz), 7.38 (1H, J˜8.4 Hz),7.60 (1H, d, J˜1.8 Hz), 7.78 (1H, dd, J˜8.4, 2.3 Hz), 8.66 (1H, d, J˜2.3Hz).

EXAMPLE 272-(2-(4,4-dimethylthiochroman-6-yl)-ethynyl)-5-pyridinecarboxaldehyde

To a cooled (-78° C.) solution of 358 mg (1.0 mmol) of2-(4,4-dimethylthiochroman-6-yl)ethynyl-5-bromopyridine in 5 ml ofanhydrous ether was added slowly under nitrogen 1.3 ml of 1.7M (2.21mmol) tert-butyl lithium in pentune. The mixture was stirred at -78° C.for 1 h and then treated with 95 mg (1.3 mmol) of anhydrousdimethylformamide. The mixture was stirred at -78° C. for a further 0.5hours, then warmed to 0° C. and treated with 5 ml of saturated NH₄ Clsolution followed by 5 ml of ether. The organic layer was separated andthe aqueous layer was extracted with ether. The organic layers werecombined, washed successively with water and saturated NaCl solution andthen dried (MgSO₄). The solvent was then removed in vacuo and theresidue purified by flash chromatography (silica; 15% ethyl acetate inhexanes) followed by high pressure liquid chromatography (Whatman M-9Partisil 10/50 column, 15% ethyl acetate in hexanes) to give the titlecompound as a pale yellow solid.

PMR (CDCl₃): δ 1.33 (6H, s), 1.93-1.97 (2H, m), 3.03-3.07 (2H, m), 7.08(1H, d, J˜8.2 Hz), 7.26 (1H, dd, J˜8.2 Hz, 1.8 Hz), 7.63-7.65 (2H, m),8.14 (2H, dd, J˜8.0 Hz, 2.3 Hz) 9.05 (1H, d, J˜2.3 Hz), 10.1 (1H, s).

EXAMPLE 282-[2-(4,4-Dimethylchroman-6-yl)ethynyl]-5-hydroxymethylpyridine

A 250 ml 3-necked flask is fitted with a stirrer, a dropping funnel, anitrogen inlet and a thermometer. In the flask is placed a solution of379.5 mg (10 mmol) of lithium aluminum hydride in 30 ml of dry diethylether. The solution is cooled to -65° C. under nitrogen and a solutionof 3.2343 g (10 mmol) of ethyl6-[2-(4,4-dimethylchroman-6-yl)ethylyl]nicotinate in 15 ml of dry etheris added dropwise at a rate such that the temperature does not exceed-60° C. The mixture is stirred at -30° C. for 1 hour and the excesshydride is then destroyed by the addition of 300 mg (3.4 mmol) of ethylacetate. The reaction mixture is then hydrolyzed by adding 3 ml ofsaturated ammonium chloride solution and allowing the temperature torise to room temperature. The mixture is then filtered and the residuewashed with ether. The ether layer is then washed with saturated sodiumchloride solution, dried (MgSO₄) and then concentrated in vacuo. Theresidue is purified by chromatography followed by recrystallization togive the title compound.

By the same process, acids or esters of this invention may be convertedto their corresponding primary alcohol.

EXAMPLE 292-[2-(4,4-Dimethylchroman-6-yl)ethynyl]-5-acetoxymethylpyridine

A solution of 2.81 g (10 mmol) of2-[2-(4,4-dimethylchroman-6-yl)ethynyl]-5-hydromymethylpyridine, 600 mg(10 mmol) of glacial acetic acid, 2.06 g (10 mmol) ofdicyclohexylcarbodiimide and 460 mg (3.765 mmol) of4-dimethylaminopyridine in 150 ml methylene chloride is stirred at roomtemperature for 48 hours. The reaction mixture is then filtered and theresidue washed with 50 ml of methylene chloride. The filtrate is thenconcentrated in vacuo and the residue is purified by chromatographyfollowed by recrystallization to give the title compound.

Proceeding in the same manner, other alcohols of this invention may beesterified.

EXAMPLE 302-(2-(4,4-Dimethylchroman-6-yl)ethynyl)pyridin-5-carboxaldehyde

A solution of 1.396 g (11 mmol) of freshly distilled oxalyl chloride in25 ml of methylene chloride is placed in a 4-necked flask equipped witha stirrer, a thermometer and two pressure-equalizing addition funnelsfitted with drying tubes. The solution is cooled to -60° C. and thentreated dropwise with a solution of 1.875 g (24 mmol) of dimethylsulfoxide (distilled from calcium hydride) in 5 ml of methylene chlorideover a five minute period. The reaction mixture is then stirred at 3160° C. for an additional 10 minutes. A solution of 2.82 (10 mmol) of2-[2-(4,4-dimethylchroman-6-yl)ethynyl]-5-hydromymethylpyridine in 10 mlof methylene chloride is then added to the reaction mixture over aperiod of 5 minutes. The mixture is stirred for a further 15 minutes andis then treated with 5.06 g (50 mmol) of triethylamine. The cooling bathis then removed and the mixture is allowed to warm to room temperature.Thirty ml of water is then added to the mixture and stirring iscontinued for a further 10 minutes. The organic layer is then separatedand the aqueous layer is extracted with 20 ml of methylene chloride. Theorganic layers are then combined and washed successively with diluteHCl, water and dilute Na₂ CO₃ solution and then dried (MgSO₄). Thesolution is then filtered and concentrated in vacuo and the residue ispurified by chromatography followed by recrystallization to give thetitle compound.

Primary alcohols of this invention may be oxidized to theircorresponding aldehyde by this method.

EXAMPLE 312-(2-(4,4-Dimethylchroman-6-yl)ethynyl)-5-(1-hydroxypropyl)pyridine

Four ml of a 3M (12 mmol) solution of ethylmagnesium bromide in ether isplaced in a 3-necked flask fitted with a mechanical stirrer, a refluxcondenser protected by a drying tube and a pressure-equalizing droppingfunnel protected by a drying tube. The flask is cooled in an ice bathand a solution of 2.8 g (10 mmol) of 2-(2-(4,4-Dimethylchroman-6-yl)ethynyl)pryidine-5-carboxaldehyde in 10 ml of dry ether is added slowlywith vigorous stirring. The cooling bath is then removed and the mixtureheated at reflux for 3 hours. The mixture is then cooled in an ice-saltbath and 5 ml of saturated ammonium chloride solution added. The mixtureis stirred for a further 1 hour and then filtered and the residue washedwith two 10 ml portions of ether. The ether solution is then separated,dried (MgSO₄) and the ether removed in vacuo. The residue is thenpurified by chromatography followed by recrystallization to give thetitle compound.

Using the same procedure any of the other aldehydes of this inventioncan be converted to a secondary alcohol.

Such secondary alcohols may be converted to their corresponding ketoneusing the procedure recited in Example 15.

EXAMPLE 322-(2-(4,4-Dimethylchroman-6-yl)ethynyl)-5-dimethoxymethylpyridine

A round-bottomed flask is fitted with a Dean-Stark apparatus under areflux condenser protected by a drying tube. A mixture of 3.35 g (12mmol) of 2-(4,4-dimethylchroman-6-yl)ethynyl)-pyridine-5-carboxaldehyde,4.80 mg (15 mmol) of anhydrous methanol, 2 mg of P-toluenesulfonic acidmonohydrate and 10 ml of anhydrous benzene is placed in the flask andthe mixture heated at reflux under nitrogen until close to thetheoretical amount of water is collected in the Dean-Stark trap. Thereaction mixture is cooled to room temperature and extractedsuccessively with 5 ml of 10% sodium hydroxide solution and two 5 mlportions of water and then dried (MgSO₄). The solution is then filteredand the solvent removed in vacuo. The residue is purified bychromatography and then recrystallization to give the title compound.

In a similar manner, any aldehyde or ketone of this invention may beconverted to an acetal or a ketal.

EXAMPLE 33

Preferably, these compounds may be administered topically using variousformulations. Such formulation may be as follows:

    ______________________________________                                        Ingredient         Weight/Percent                                             ______________________________________                                        Solution                                                                      Retinoid           0.1                                                        BHT                0.1                                                        Alcohol USP        58.0                                                       Polyethylene Glycol 400 NF                                                                       41.8                                                       Gel                                                                           Retinoid           0.1                                                        BHT                0.1                                                        Alcohol USP        97.8                                                       Hydroxypropyl Cellulose                                                                          2.0                                                        ______________________________________                                    

What is claimed is:
 1. A compound of the formula ##STR11## where X is Sor O; R is hydrogen or lower alkyl; A is pyridazinyl, pyrimidinyl orpyrazinyl; n is 0-4; and B is H, --COOH or a pharmaceutically acceptablesalt thereof, or an ester thereof with a saturated aliphatic alcohol often or fewer carbon atoms, or with a cyclic or saturated aliphaticcyclic alcohol of 5 to 10 carbon atoms, or with phenol or with a loweralkylphenol, or an amide or a mono or di-substituted amide thereof, thesubtituents on the amide being selected from a group consisting ofsaturated aliphatic radicals of ten or fewer carbon atoms, cyclic orsaturated aliphatic cyclic radicals of 5 to 10 carbon atoms, and phenylor lower alkylphenyl radicals, or B is CH₂ OH or an ester derivativethereof derived from a saturated aliphatic acid of ten or fewer carbonatoms, or from a cyclic or saturated aliphatic cyclic acid of 5 to 10carbon atoms, or from benzoic acid, or an ether derivative thereofderived from a saturated aliphatic radical of ten or fewer carbon atoms,or from a cyclic or saturated aliphatic cyclic radical of 5 to 10 carbonatoms, or from phenyl or lower alkylphenyl radical, or B is --CHO or alower alkyl acetal derivative thereof, or an acetal derivative thereofformed with a lower alkyl diol, or B is --COR₁ or a lower alkyl ketalderivative thereof, or a ketal derivative thereof formed with a loweralkyl diol, where R₁ is --(CH₂)_(m) CH₃ where m is 0-4, or apharmaceutically acceptable salt of the compound defined in saidformula.
 2. A compound of claim 1 where X is S.
 3. A compound of claim 1where X is O.
 4. A compound of claim 3 where A is pyridazinyl.
 5. Acompound of claim 2 where A is pyrimidinyl.
 6. A compound of claim 2where A is pyrazinyl.
 7. A compound of claim 3 where A is pyrazinyl. 8.A compound of claim 2 where A is pyrimidinyl and B is --CH₂ OH or alower alkyl ether or lower alkyl acid ester thereof.
 9. A compound ofclaim 2 where A is pyrimidinyl and B is --CHO or an acetal derivativethereof.
 10. A compound of claim 2 where A is pyridazinyl.
 11. Acompound of claim 3 where A is pyrimidinyl.
 12. A compound of claim 5which is ethyl5-(4,4-dimethylthiochroman-6-yl)ethynyl-pyrimidin-2-yl-acetate,5-(4,4-dimethylthiochroman-6-yl)ethynyl-pyrimidin-2-yl-acetic acid,ethyl 5-(4,4-dimethylthiochroman-6-yl)ethynyl-pyrimidin-2-yl-pentanoate,5-(4,4-dimethylthiochroman-6-yl)ethynyl-pyrimidin-2-yl-pentanoic acid,or a pharmaceutically acceptable salt thereof.
 13. A compound of claim 5which is ethyl5-(4,4,7-trimethylthiochroman-6-yl)ethynyl-pyrimidin-2-yl-acetate,5-(4,4,7-trimethylthiochroman-6-yl)ethynyl-pyrimidin-2-yl-acetic acid,ethyl5-(4,4,7-trimethylthiochroman-6-yl)ethynyl-pyrimidin-2-yl-pentanoate,5-(4,4,7-trimethylthiochroman-6-yl)ethynyl-pyrimidin-2-yl-pentanoicacid, or a pharmaceutically acceptable salt thereof.
 14. A compound ofclaim 4 which is ethyl5-(4,4-dimethylchroman-6-yl)ethynyl-pyridazin-3-yl-acetate,5-(4,4-dimethylchroman-6-yl)ethynyl-pyridazin-3-yl-acetic acid, ethyl5-(4,4-dimethylchroman-6-yl)ethynyl-pyridazin-3-yl-pentanoate,5-(4,4-dimethylchroman-6-yl)ethynyl-pyridazin-3-yl-pentanoic acid, ethyl5-(4,4,7-trimethylchroman-6-yl)ethynyl-pyridazin-3-yl-acetate,5-(4,4,7-trimethylchroman-6-yl)ethynyl-pyridazin-3-yl-acetic acid, ethyl5-(4,4,7-trimethylchroman-6-yl)ethynyl-pyridazin-3-yl-pentanoate,5-(4,4,7-trimethylchroman-6-yl)ethynyl-pyridazin-3-yl-pentanoic acid ora pharmaceutically acceptable salt thereof.
 15. A compound of claim 6which is ethyl5-(4,4-dimethylthiochroman-6-yl)ethynyl-pyrazin-3-yl-acetate,5-(4,4-dimethylthiochroman-6-yl)ethynyl-pyrazin-3-yl-acetic acid, ethyl5-(4,4-dimethylthiochroman-6-yl)ethynyl-pyrazin-3-yl-pentanoate,5-(4,4-dimethylthiochroman-6-yl)ethynyl-pyrazin-3-yl-pentanoic acid, ora pharmaceutically acceptable salt thereof.
 16. A compound of claim 6which is ethyl5-(4,4,7-trimethylthiochroman-6-yl)ethynyl-pyrazin-3-yl-acetate,5-(4,4,7-trimethylthiochroman-6-yl)ethynyl-pyrazin-3-yl-acetic acid,ethyl5-(4,4,7-trimethylthiochroman-6-yl)ethynyl-pyrazin-3-yl-pentanoate,5-(4,4,7-trimethylthiochroman-6-yl)ethynyl-pyrazin-3-yl-pentanoic acid,or a pharmaceutically acceptable salt thereof.
 17. A compound of claim10 which is ethyl5-(4,4-dimethylthiochroman-6-yl)ethynyl-pyridazin-3-yl-acetate,5-(4,4-dimethylthiochroman-6-yl)ethynyl-pyridazin-3-yl-acetic acid,ethyl 5-(4,4-dimethylthiochroman-6-yl)ethynyl-pyridazin-3-yl-pentanoate,5-(4,4-dimethylthiochroman-6-yl)ethynyl-pyridazin-3-yl-pentanoic acid,ethyl 5-(4,4,7-trimethylthiochroman-6-yl)ethynyl-pyridazin-3-yl-acetate,5-(4,4,7-trimethylthiochroman-6-yl)ethynyl-pyridazin-3-yl-acetic acid,ethyl5-(4,4,7-trimethylthiochroman-6-yl)ethynyl-pyridazin-3-yl-pentanoate,5-(4,4,7-trimethylthiochroman-6-yl)ethynyl-pyridazin-3-yl-pentanoic acidor a pharmaceutically acceptable salt thereof.
 18. A compound of claim11 which is ethyl5-(4,4-dimethylchroman-6-yl)ethynyl-pyrimidin-2-yl-acetate,5-(4,4-dimethylchroman-6-yl)ethynyl-pyrimidin-2-yl-acetic acid, ethyl5-(4,4-dimethylchroman-6-yl)ethynyl-pyrimidin-2-yl-pentanoate,5-(4,4-dimethylchroman-6-yl)ethynyl-pyrimidin-2-yl-pentanoic acid, ethyl5-(4,4,7-trimethylchroman-6-yl)ethynyl-pyrimidin-2-yl-acetate,5-(4,4,7-trimethylchroman-6-yl)ethynyl-pyrimidin-2-yl-acetic acid, ethyl5-(4,4,7-trimethylchroman-6-yl)ethynyl-pyrimidin-2-yl-pentanoate,5-(4,4,7-trimethylchroman-6-yl)ethynyl-pyrimidin-2-yl-pentanoic acid, ora pharmaceutically acceptable salt thereof.
 19. A compound of claim 7which is ethyl 5-(4,4-dimethylchroman-6-yl)ethynyl-pyrazin-3-yl-acetate,5-(4,4-dimethylchroman-6-yl)ethynyl-pyrazin-3-yl-acetic acid, ethyl5-(4,4-dimethylchroman-6-yl)ethynyl-pyrazin-3-yl-pentanoate,5-(4,4-dimethylchroman-6-yl)ethynyl-pyrazin-3-yl-pentanoic acid, ethyl5-(4,4,7-trimethylchroman-6-yl) ethynyl-pyrazin-3-yl-acetate,5-(4,4,7-trimethylchroman-6-yl)ethynyl-pyrazin-3-yl-acetic acid, ethyl5-(4,4,7-trimethylchroman-6-yl)ethynyl-pyrazin-3-yl-pentanoate, 5-(4,4,7-trimethylchroman-6-yl) ethynyl-pyrazin-3-yl-pentanoic acid, or apharmaceutically acceptable salt thereof.
 20. A pharmaceuticalcomposition comprising a pharmaceutically acceptable excipient and acompound of the formula ##STR12## where X is S or O; R is hydrogen orlower alkyl; A is pyridazinyl, pyrimidinyl or pyrazinyl; n is 0-4; and Bis H, --COOH or a pharmaceutically acceptable salt thereof, or an esterthereof with a saturated aliphatic alcohol of ten or fewer carbon atoms,or with a cyclic or saturated aliphatic cyclic alcohol of 5 to 10 carbonatoms, or with phenol or with a lower alkylphenol, or an amide or a monoor di-substituted amide thereof, the subtituents on the amide beingselected from a group consisting of saturated aliphatic radicals of tenor fewer carbon atoms, cyclic or saturated aliphatic cyclic radicals of5 to 10 carbon atoms, and phenyl or lower alkylphenyl radicals, or B isCH₂ OH or an ester derivative thereof derived from a saturated aliphaticacid of ten or fewer carbon atoms, or from a cyclic or saturatedaliphatic cyclic acid of 5 to 10 carbon atoms, or from benzoic acid, oran ether derivative thereof derived from a saturated aliphatic radicalof ten or fewer carbon atoms, or from a cyclic or saturated aliphaticcyclic radical of 5 to 10 carbon atoms, or from phenyl or loweralkylphenyl radical, or B is --CHO or a lower alkyl acetal derivativethereof, or an acetal derivative thereof formed with a lower alkyl diol,or B is --COR₁ or a lower alkyl ketal derivative thereof, or a ketalderivative thereof formed with a lower alkyl diol, where R₁ is--(CH₂)_(m) CH₃ where m is 0-4, or a pharmaceutically acceptable salt ofthe compound defined in said formula.
 21. A composition according toclaim 20 useful for treating psoriasis in a mammal.
 22. A method oftreating psoriasis in a mammal which method comprises administeringalone or in conjunction with a pharmaceutically acceptable excipient, atherapeutically effective amount of a compound of the formula ##STR13##where X is S or O; R is hydrogen or lower alkyl; A is pyridazinyl,pyrimidinyl or pyrazinyl; n is 0-5; and B is H, --COOH or apharmaceutically acceptable salt thereof, or an ester thereof with asaturated aliphatic alcohol of ten or fewer carbon atoms, or with acyclic or saturated aliphatic cyclic alcohol of 5 to 10 carbon atoms, orwith phenol or with a lower alkylphenol or an amide or a mono ordi-substituted amide thereof, the subtituents on the amide beingselected from a group consisting of saturated aliphatic radicals of tenor fewer carbon atoms, cyclic or saturated aliphatic cyclic radicals of5 to 10 carbon atoms, and phenyl or lower alkylphenyl radicals, or B isCH₂ OH or an ester derivative thereof derived from a saturated aliphaticacid of ten or fewer carbon atoms, or from a cyclic or saturatedaliphatic cyclic acid of 5 to 10 carbon atoms, or from benzoic acid, oran ether derivative thereof derived from a saturated aliphatic radicalof ten or fewer carbon atoms, or from a cyclic or saturated aliphaticcyclic radical of 4 to 10 carbon atoms, or from phenyl or loweralkylphenyl radical, or B is --CHO or a lower alkyl acetal derivativethereof, or an acetal derivative thereof formed with a lower alkyl diol,or B is --COR₁ or a lower alkyl ketal derivative thereof, or a ketalderivative thereof formed with a lower alkyl diol, where R₁ is--(CH₂)_(m) CH₃ where m is 0-4, or a pharmaceutically acceptable salt ofthe compound defined in said formula.